EXCHANGE 


Investigation  in  the  Thiazole  Field* 

The  Synthesis  of  an  Analog 

of  Cinchophen 

(ATOPHAN) 


DISSERTATION 


SUBMITTED  IN  PARTIAL  FULFILLMENT  OF  THE  RE- 
QUIREMENTS FOR  THE  DEGREE  OF  DOCTOR  OF 
PHILOSOPHY  IN  THE  FACULTY  OF  PURE 
SCIENCE  OF  COLUMBIA  UNIVERSITY 


BY 

EMANUEL  M.  ABRAHAMSON,  B.S.,  Ch.E.,  M.A 

NEW  YORK  CITY 
1922 


Investigation  in  the  Thiazole  Field. 

The  Synthesis  of  an  Analog 

of  Cinchophen 

(ATOPHAN) 


DISSERTATION 


SUBMITTED  IN  PARTIAL  FULFILLMENT  OF  THE  RE- 
QUIREMENTS FOR  THE  DEGREE  OF  DOCTOR  OF 
PHILOSOPHY  IN  THE  FACULTY  OF  PURE 
SCIENCE  OF  COLUMBIA  UNIVERSITY 


BY 

EMANUEL  M.  ABRAHAMSON,  B.S.,  Ch.E.,  M.A. 

\^ 

NEW  YORK  CITY 
1922 


TO  THE  MEMORY 

OF 
MY  FATHER 


-  «-  o  -»  I  O 


ACKNOWLEDGMENT 

The  author  desires  to  express  his  gratitude  to  Professor  Marston  Taylor 
Bogert,  who  suggested  this  work  and  under  whose  direction  it  was  com- 
pleted. Whatever  merit  this  research  may  have  is  due  to  his  kindly 
criticism,  suggestions,  and  assistance. 


ABSTRACT  OF  DISSERTATION. 

Cyclicly  bound  sulfur  has  the  effect  of  causing  a  marked  rise  in  resorp- 
tion,  i.  e.  the  reabsorption  by  the  system  of  material  previously  separated 
out.  A  synthesis  of  a  sulfur  compound  somewhat  analogous,  structurally, 
to  a-phenyl  cinchoninic  acid  was  attempted  in  order  to  add  the  effect  of 
nuclear  sulfur  to  the  uric  acid  solvent  action  of  atophan.  The  compound 
prepared  was  2-phenyl,  benzothiazole  carboxylic  acid-6.  It  was  made  by 
nitrating  /z-phenyl  benzothiazole, 


s/2 

7  1 

reducing  to  the  amine,  and  converting  the  latter  into  the  acid  by  the 
Sandmeyer  reaction. 

The  position  of  the  amino  group,  and  therefore  of  the  carboxyl,  was 
shown  by  the  conversion  of  the  amine  into/*,  ju'  -diphenyl  benzobisthiazole, 
a  compound  previously  synthesized  from  para-phenylene  diamine. 

The  action  of  halogens  on  ju-phenyl  benzothiazole  was  also  studied.  It 
forms  an  unstable  tetrabrom  addition  product,  which  readily  loses  its 
bromine,  the  liberated  bromine  then  substituting  the  6-hydrogen  to  give 
a  brom  derivative  which  can  also  be  obtained  from  the  amine  by  the  Gat- 
terman  reaction.  The  compound,  on  the  other  hand,  adds  but  two 
atoms  of  iodine. 

Curiously,  it  was  found  impossible  to  prepare  an  aldehyde  or  a  ketone 
by  the  Gatterman-Koch  or  Friedel  and  Crafts  reactions.  These  compounds 
would  be  interesting  in  that  the  effect  of  the  odoriferous  groups  on 
the  slightly  fragrant  /z-phenyl  benzothiazole  might  produce  a  perfume. 

In  the  course  of  this  research  the  following  compounds,  hitherto  un- 
known, were  prepared : 

6-amino,  2-phenyl  benzothiazole* 

6-benzylideneamino,  2-phenyl  benzothiazole 

6-acetamino,  2-phenyl  benzothiazole 

Para-nitro  benzene-azo-6-amino,  2-phenyl  benzothiazole 

Para-nitro  benzene-azo-6-acetamino,2-phenyl  benzothiazole 

v-iJ.  '-diphenyl  benzobisthiazole  t 

Nitro,  p,fji  '-diphenyl  benzobisthiazole 

Amino,  /*,/* '-diphenyl  benzobisthiazole  , 

Acetamino,  ^u./z'-diphenyl  benzobisthiazole 

6-dimethylamino,  2-phenyl  benzothiazole 

ju-phenyl  benzothiazole  tetrabromide 

ju-phenyl  benzothiazole  di-iodide 

6-brom,  2-phenyl  benzothiazole  t 

N-acetyl,  chlor,  2-phenyl  benzothiazole 

2-phenyl  benzothiazole  carboxylic  acid-6 

Methyl  ester  of  2-phenyl  benzothiazole  carboxylic  acid-6 

*  Previously  prepared  but  not  analyzed. 

t  Prepared  previously  but  by  an  entirely  different  synthesis. 

%  Prepared  in  this  work  by  two  different  methods. 


• 


INVESTIGATION  IN  THE  THIAZOLE  FIELD.     THE  SYNTHESIS 
OF  AN  ANALOG  OF  CINCHOPHEN  (ATOPHAN) 

Introductory 

The  Organic  Laboratory  of  Columbia  University  has  had  under  way 
for  some  time  a  number  of  investigations  in  the  thiazole  field,  the  re- 
sults of  which  it  hopes  to  publish  as  rapidly  as  opportunity  permits. 

The  plan  adopted  for  numbering  the  positions  on  the  thiazole  and  ben- 
zo thiazole  nuclei  both  in  Richter's  "Lexikon"  and  in  the  Decennial  Index 
to  Chemical  Abstracts  is  as  indicated  in  Formulas  I  and  II.  This  lack 
of  uniformity  seems  to  us  highly  undesirable  and  confusing.  Therefore, 
we  have  employed  consistently  throughout  this  paper  the  numbering  given 
in  Formulas  III  and  IV,  so  that  S  is  always  in  position  1  and  N  at  3,  while 
the  C  at  2  occupies  the  /u-,  or  middle  position.  This  is  in  agreement  with 
the  system  adopted  in  the  new  (2nd)  edition  of  Meyer- Jacobson's  "Lehr- 
buch  der  organischen  Chemie.1" 

/s\  «/\/8\    /s\  ./\/sl\ 


c,  ,c        c  c, 

I  I 

r*              TVT                                *               r*  XT 

4C NI  «C Na 

I  II  III  IV 

For  the  experiments  described  in  this  first  paper,  2-phenyl-benzo  thia- 
zole has  served  as  initial  niaterial,  and  from  this  interesting  substance 
various  derivatives  have  been  prepared  and  studied. 

Of  the  many  methods  of  preparing  this  compound  already  given 
in  the  literature,2  we  have  found  fusion  of  benzanilide  or  benzalaniline 

1  Vol.  II,  Part  3,  Sec.  2,  pp.  535  and  549. 

2  Ber.,  10,  2135  (1877) ;  12,  2360  (1879) ;  13,  8,  17,  1223,  1236  (1880) ;  15,  2033  (1882)  ; 
19,  1068,  1069  (1886);  23,  2476  (1890);  35,  1946  (1902);  44,  3037  (1911);  48,  1244, 
1251  (1915).  Ann.,  259,  301  (1890).  Am.  Chem.  J.,  17,  1401  (1895).  Ger.  pat. 
51,172  and  55,222;  Friedldnder,  2,  301,  302  (1891) 


with  sulfur  the  most  satisfactory.     This  is  the  more  economical  and  ex- 
peditious method,  although  the  crude  product  is  usually  slightly  colored . 

Perhaps  the  most  remarkable  physical  property  of  this  thiazole,  es- 
pecially since  it  is  an  unoxidized  sulfur  compound,  is  its  very  agreeable 
odor,  recalling  that  of  tea  roses  or  the  rose  geranium,  so  that  it  has  been 
known  also  as  "Rosenkorper."  This  odor  has  not  been  encountered 
in  similar  strength  in  any  of  its  homologs  or  derivatives. 

Our  experiments  have  disclosed  another  peculiarity,  namely,  its  failure 
to  react,  in  solution  in  carbon  disulfide,  with  aluminum  chloride,  so  that 
neither  the  Friedel  and  Crafts  nor  Gattermann-Koch  reaction  is  avail- 
able for  the  production  of  derivatives.  In  both  cases,  the  thiazole  is  re- 
covered practically  unaltered.  Further  experiments  are  under  way  in 
this  direction,  however,  as  it  has  been  shown  in  other  cases  that  carbon 
disulfide  occasionally  inhibits  these  reactions. 

It  is  difficult  to  understand  Hofmann's  statement3  that  fuming  nitric 
acid  is  without  action  upon  2-phenyl-benzothiazole,  for  we  have  found 
that  this  compound  is  nitrated  with  the  greatest  ease  by  fuming  nitric 
acid,  as  well  as  by  a  mixture  of  nitric  and  sulfuric  acids,  to  give  nearly 
theoretical  yields  of  the  nitro  compound.  Hofmann3  did  nitrate  it  with 
mixed  acids  and  obtained  the  same  nitro  derivative  as  that  described 
by  us  (m.  p.  188°).  His  analysis  showed  it  to  be  a  mononitro  derivative, 
but  he  did  not  determine  the  position  of  the  nitro  group.  Naegeli4  also 
nitrated  the  compound  with  mixed  acids  with  similar  results.  He  then 
fused  this  nitro  derivative  with  potassium  hydroxide  and  from  the  melt 
separated  a  substance,  m.  p.  234-6°,  soluble  in  sodium  carbonate  solution 
which  was  re-precipitated  by  mineral  acid  and  could  be  reduced  by  tin 
and  hydrochloric  acid  to  an  amino  compound.  These  and  other  properties 
seemed  to  agree  with  those  of  ^-nitrobenzoic  acid  (m.  p.  238°).  He  states 
that  the  results  of  the  fusion  were  very  unsatisfactory,  the  yield  of  p- 
nitrobenzoic  acid  being  poor,  and  that  there  was  extensive  decomposition 
and  carbonization.  On  the  basis  of  this  result,  he  assigned  the  nitro 
group  a  position  in  the  2-phenyl  radical  para  to  the  ju-carbon  of  the  thia- 
zole nucleus.  We  have  repeated  Naegeli's  experiments  with  the  nitro 
compound,  but  were  unable  to  isolate  any  crystalline  products  from  the 
resultant  tar. 

Hofmann3  noted  that  this  nitro  derivative  could  be  readily  reduced 
to  a  crystalline  amine,  whose  hydrochloride  was  also  crystalline5    Remy, 
Erhart  and  Co.  state  that  this  hydrochloride  is  difficultly  soluble.     The 
patent  covers   the  azo  dyes    made  from  the    amine,  although  no  data 
whatever  are  given  concerning   the   amine   itself,  or   the   method  of  its 
8  Hofmann,  Ber.,  13,  1223  (1880). 
4  Naegeli,  Bull.  soc.  chim.,  [3]  11,  895  (1894). 
6  Ger.  pat.,  57,557;  Friedldnder,  3,  750  (1896). 


8 

preparation.  We  have  found  that  reduction  with  tin  and  hydrochloric 
acid  occurs  smoothly  and  that  the  pure  amine  melts  at  207°  (corn), 
whereas  French  patent  216,0866  gives  the  melting  point  of  £-aminophenyl- 
benzothiazole  as  154-155°.  There  does  not  seem  to  be  much  doubt 
concerning  the  structure  of  the  latter  amine,  since  it  was  prepared  by 
fusion  of  a  mixture  of  aniline,  p-toluidine  and  sulfur  at  180-250°;  and 
its  use  for  the  manufacture  of  azo  dyes  was  also  patented.7  It  has 
also  been  shown  that  the  nitration  of  amino  benzothiazoles  gives  nitro 
derivatives  with  the  nitro  group  in  the  benzothiazole  benzene  nucleus, 
and  not  in  the  2-phenyl  radical.8 

It  appeared  most  unlikely,  therefore,  that  direct  nitration  of  2-phenyl- 
benzothiazole  would  yield  a  derivative  with  its  nitro  group  in  the  2-phenyl 
nucleus.  To  prove  the  point,  the  amine  was  fused  with  caustic  alkali, 
a  reaction  which  proceeds  much  more  smoothly  than  that  with  the  corre- 
sponding nitro  derivative.  Benzoic  acid  itself  was  separated  as  the 
main  product  of  this  fusion.  It  follows  from  this  that  the  amino  group, 
and  consequently  the  nitro  group,  must  have  been  on  the  benzothiazole 
nucleus  and  not  on  the  2-phenyl  nucleus. 

>  H,N.CeH/  +  C9H6.COOH. 


A  single  attempt  to  isolate  and  identify  the  diamino-thiophenol,  which 
should  be  the  other  main  product  of  the  fusion,  was  unsuccessful,  and  no 
further  efforts  were  made,  since  the  absence  of  any  aminobenzoic  was 
demonstrated,  and  this  was  deemed  sufficient  proof  of  the  position  of  the 
nitro  group. 

As  5-amino-2-phenyl-benzothiazole  has  been  described  already,9  and 
is  not  identical  with  the  amine  in  question,  the  remaining  possibilities 
are  the  4-,  6-  or  7-amino  derivatives.  The  following  experimental  work 
led  to  a  choice  among  these  possibilities. 

It  has  been  observed  frequently  that  an  aromatic  amine  with  free 
para  and  ortho  positions,  when  treated  with  a  diazonium  salt  under  proper 
conditions,  will  couple  twice,  first  in  the  para  and  then  in  the  ortho  position. 
Thus  the  4-  or  7-amino  compound  (V  and  VII)  should  couple  twice,  and 
the  6-amino  derivative  (VI)  but  once, 

H>NWS\ 

C.C«H6  I   •        C.C6He 


NH2 

V  VI 


•  Winther,  3,  379   (1910). 

7  Ger.  pat.  79,214;  Friedldnder  ;  4,  829  (1899). 

8  Ger.  pat.  81,711;  Friedldnder,  4,  831    (1899). 

9  Kym,  Ber.,  32,  3534  (1899)  ;  Ger.  pat.  75,674;  Friedldnder,  4,  826  (1899). 


With  diazotized  ^-nitro-aniline,  the  new  amine  was  found  to  couple  but 
once.  The  conclusion  that  it  was,  therefore,  the  6-amino  derivative  was 
further  corroborated  by  converting  it  into  its  benzal  derivative  and  fusing 
the  latter  with  sulfur,  when  a  benzobisthiazole  was  obtained  identical 
with  that  secured  by  Green  and  Perkin10  from  ^-phenylenediamine  di- 
thiosulfonic  acid  and  benzaldehyde,  to  which  they  assigned  Formula 
VIII, 

NHa 

C6H6.C  C.CeH* 

" 


CeHs.C  C.C6HS. 


VIII  IX 

This  benzobisthiazole  was  also  nitrated,  the  resulting  nitro  derivative 
reduced  to  the  amine  and  the  amine  fused  with  caustic  alkali.  Only 
benzoic  acid  was  isolated,  and  no  aminobenzoic,  thus  locating  the  (nitro* 
and)  amino  group  on  the  middle  benzene  nucleus  (IX). 

No  dinitro-2-phenyl  derivatives  were  encountered  in  our  experiments. 
Such  compounds  have  been  described,  however,11  and  from  them  diamines 
(m.  p.  192°,  208°  and  255-256°)  prepared,  as  well  as  azo  dyes  from  the 
latter.12 

6-Amino-2-phenyl-benzothiazole  methylated  under  pressure  with  methyl 
alcohol  and  hydrochloric  acid  gave  only  the  tertiary  compound, 
but  no  quaternary  salt.  This  reaction  is  being  examined  further,  es- 
pecially in  its  bearing  upon  the  formation  and  tinctorial  properties  of  the 
thioflavines. 

By  means  of  the  Sandmeyer  reaction,  the  amino  compound  was  changed 
to  the  corresponding  nitrile  and  the  latter  saponified  to  the  acid  (XIII). 

Quinoline  is  stated  to  have  very  powerful  antiseptic,  antipyretic  and 
antizymotic  action,  but  is  too  toxic  and  causes  collapse.  Sulfur  in  cyclic 
union,  as  in  thiophene,  ichthyol,  etc.,  in  addition  to  its  antiseptic  and 
antiparasitic  properties,  causes  a  marked  increase  in  resorption,  resembling 
iodine  in  this  respect,  although  in  no  way  similar  to  that,  pharmacologically. 
Cyclic  compounds  containing  substituted  sulfur  also  show  striking  anal- 
gesic properties  which  can  be  ascribed  only  to  the  entry  of  sulfur  into  such 
groups.  Quinoline,  itself,  a  strong  protoplasmic  poison,  on  fusion  with 


sulfur  gives  the  so-called  "thioquinanthrene,"  NC9H6<r      yCgHsN,  which 

S 
is  inert  physiologically.     In  cyclic  systems,  one  sulfur  atom  appears  to 

10  Green  and  Perkin,  J.  Chem.  Soc.,  83,  1207  (1903). 

11  Ger.  pat.  50,486;  Friedldnder,  2, 303  (1891) ; and 54,921 ;  Fnedldnder,  2, 305  (1891). 

12  See  also  Ger.  pat.  58,641 ;  Friedldnder,  3,  765  (1896). 


10 

have  much  the  same  effect  as  an  ethylene  group,  —  CH :  CH  — ,  an  analogy 
well  illustrated  by  comparison  of  corresponding  members  of  the  benzene 
and  thiophene  series.  The  benzothiazoles  (XI)  are,  therefore,  the  parallels 
to  the  quinolines  (X),  and  show  many  striking  points  of  similarity  in 
their  chemical  behavior.  Hence,  the  new  acid  noted  above  (XIII) 
may  show  some  of  the  valuable  properties  of  the  well-known  a-phenyl- 
cinchoninic  acid  (Cinchophen,  or  Atophan)  (XII)  as  a  remedy  for  gout. 
If  the  presence  of  sulfur  in  the  complex  should  really  prove  to  increase 
resorption,  this  should  be  a  valuable  adjunct  to  a  uric  acid  eliminant. 
It  is  hoped  to  test  experimentally  its  therapeutic  possibilities. 


C.C,HS 


XII  XIII 


According  to  Ciusa  and  Luzzatto18  most  of  the  physiological  action  of 
2-phenyl-cinchoninic  acid  is  due  to  the  2-phenyl  group,  and  this  appears 
to  be  borne  out  by  the  fact  that  the  following  compounds  show  practically 
the  same  effect  as  cinchophen  itself:  its  methyl  or  ethyl  (Acitrin)  esters, 
6-methyl-2-phenyl-cinchoninic  acid  (Paratophan),  the  methyl  (Novato- 
phan  K)  or  ethyl  (Neocinchophen,  Novatophan)  esters  of  the  latter, 
8-methoxy-2-phenyl-cinchoninic  acid  (Isatophan),  cinchophen  salicylate, 
2-phenylquinoline-4-diethyl  carbinol,  2-phenyl-/3-naphthoquinoline-7-car- 
boxylic  acid  (Diapurin),  while  cinchoninic  acid,  itself,  is  inactive.  Modi- 
fications of  the  2-phenyl  group  by  substitution  of  H  by  OH,  OR  or  NR.2 
groups,  seems  to  reduce  the  usefulness  of  the  drug.  The  2'-COOH  de- 
rivative prepared  by  Reissert  and  Holle14  in  1911  is  therefore  likely  to 
show  a  different  behavior  physiologically  from  that  of  the  isomer  carrying 
the  COOH  group  on  the  other  benzene  nucleus,  even  though  the  main 
function  of  this  group  is  simply  to  render  the  complex  more  easily  solu- 
ble. No  record  has  been  found  of  any  physiological  experiments  with  the 
product  described  by  Reissert  and  Holle;  it  was  not  prepared  with  any 
such  object  in  view,  since  it  was  merely  incidental  to  a  study  of  thio- 
phthalanil. 

In  acetic  acid  solution,  2-phenyl -benzothiazole  takes  up  4  atoms  of  bro- 
mine per  mole  of  thiazole;  red  crystals  of  the  tetrabromo  addition  product 
Ci3H9NSBr4  separate.  This  behavior  parallels  that  of  the  analogous 
selenium  compound,  which  also  adds  4  bromine  atoms.  Fromm  and 
18  Ciusa  and  Luzzatto,  Atti  accad.  Lined,  [5]  22, 1,  305  (1913) ;  Gazz.  chim,  ital.,  44, 
I,  64  (1914);  Zentr.,  1913,  II,  1318. 

"  Reissert  and  Holle,  Ber.,  44, 3035  (1911). 


11 

/N(Br,k' 

Martin16  assigned  the  structure  C6H4\  ^C.C6H5  to  the  product, 

\Se(Br2K 

basing  this  conclusion  on  the  ease  with  which  the  bromine  could  be  dis- 
placed and  the  parent  selenazole  regenerated.  The  bromine  addition 
product  of  2-phenyl-benzothiazole  is  less '  stable  than  the  corresponding 
selenazole  compound,  since  it  loses  bromine  even  on  standing  at  ordinary 
temperature.  This  is  in  line  with  the  lower  basicity  of  sulfur.  When 
heated  in  2 : 1  acetic  acid,  the  solution  suddenly  turns  colorless  and  white 
crystals  of  a  monobromo  substitution  product,  Ci3H8NSBr,  are  deposited 
as  the  solution  cools.  This  bromo  derivative  was  proved  to  be  the 
6-bromo  compound  by  preparing  the  same  substance  from  the  6-amino 
derivative  through  the  diazo  reaction.  This  is  similar  to  the  transition 
of  benzalaniline  dibromide  to  benzal  ^-bromo-aniline  and  hydrochloric 
acid.16 

Iodine  also  forms  an  unstable  addition  product  with  2-phenyl-benzo- 
thiazole, from  which  sodium  thiosulfate  removes  the  halogen  quanti- 
tatively, thus  affording  a  convenient  method  of  analysis.  Unlike  the 
analogous  selenazole,  only  2  atoms  of  iodine  are  added  per  mole  of  thia- 
zole,  instead  of  4,  a  behavior  also  in  harmony  with  the  weaker  basicity 
of  sulfur.  As  this  addition  product  contains  about  50%  of  iodine  by  weight, 
it  offers  possibilities  as  an  iodoform  substitute,  since  it  may  combine  the 
action  of  nuclear  sulfur  with  that  of  the  iodine. 

Like  quinoline,  2-phenyl-benzothiazole  dissolved  in  toluene  adds  acetyl 
chloride  readily;  the  product  is  decomposed  immediately  by  water  or 
on  application  of  heat. 

Other  experimental  work  under  way  with  this  thiazole  relates  to  its 
reduction,  the  behavior  of  the  6-amino  derivative  when  subjected  to  such 
ordinary  aniline  reactions  as  lead  to  the  corresponding  quinoline,  the 
cinchophen  (Atophan)  (i.  e.,  from  the  6-benzalamino  derivative  and  py- 
ruvic  acid),  the  phenol,  various  dyes,  etc.,  and  will  be  reported  later. 

Experimental  Part 

2-Phenyl-benzothiazole,  Ci3H9NS. — (a).  From  Benzanilide. — The  Hofmann  proc- 
ess3 was  employed  with  a  few  modifications.  Five  hundred  g.  of  benzanilide  and  200  g. 
of  sulfur  (2.5  equivalents)  were  fused  together  at  250-260°  until  evolution  of  steam  ceased. 
The  melt  was  then  distilled  under  diminished  pressure  from  2  Pyrex  flasks  with  side  tubes 
sealed  together.  The  main  distillate  which  came  over  at  220°  at  19  mm.  was  cooled, 
pulverized  and  boiled  for  an  hour  under  a  reflux  condenser  with  one  liter  of  hot  cone, 
hydrochloric  acid.  The  yellow  acid  extract  was  filtered  hot  through  asbestos,  and  the 
filtrate  added  to  6  liters  of  cold  water.  After  the  precipitated  thiazole  was  crystallized 
from  alcohol,  it  melted  at  114°  (corr.).  'Yield,  400  g.  or  75%. 

15  Fromm  and  Martin,  Ann.,  401, 1781  (1913). 
se  Hantzsch,  Ber.,  23,  2774  (1890), 


12 

(&).  From  Benzalaniline. — This  is  also  a  modification  of  a  method  already  in  the 
literature. 17  Five  hundred  g.  of  benzalaniline,  prepared  by  mixing  equal  moles  of  benzal- 
dehyde  and  aniline  and  heating  the  mixture  at  120-130°  until  all  water  was  removed,  was 
heated  with  200  g.  of  sulfur  (2.25  equivs.)  at  250-260°  until  no  more  hydrogen  sulfide 
was  evolved,  and  the  heating  then  continued  for  2  hours  longer  under  reduced  pressure. 
The  crude  melt,  purified  as  above,  gave  a  yield  of  pure  product  (m.  p.  114°)  amounting 
to  375  g.  or  64%.  With  either  of  the  above  methods,  when  the  temperature  rises  much 
higher  than  that  given  the  yield  is  diminished  considerably.  Distillation  under  dimin- 
ished pressure  is  the  quickest  way  to  secure  a  colorless  product,  but  is  troublesome. 
The  substance  obtained  by  extracting  the  crude  melt  directly  with  hot  cone,  hydro- 
chloric acid,  when  purified  as  indicated  above,  melts  at  practically  the  same  point  (114°), 
although  it  often  has  a  pale  yellowish  cast.  For  most  purposes,  therefore,  the  undis- 
tilled  product  is  entirely  suitable. 

The  second  method  has  been  found  to  be  the  more  rapid,  economical  and  convenient, 
although  the  crude  product  from  benzanilide  is  apt  to  be  rather  lighter  in  color. 

6-Nitro-2-phenyl-benzothiazole,  CifH8NS(NOJ).— After  21  g.  (0.1  mole)  of  the 
thiazole  was  added  slowly  to  150  cc.  of  fuming  nitric  acid  (sp.  gr.  1.60),  the  solution 
was  allowed  to  stand  for  half  an  hour  and  then  poured  into  500  cc.  of  cold  water.  The 
precipitated  nitro  derivative  was  collected  and  crystallized  from  glacial  acetic  acid. 
M.  p.  188°  (corr.).  Yield,  24  g.,  or  94%. 

In  another  series  of  experiments  we  followed  in  the  main  the  process  of  Naegeli.4 
Twenty  one  g.  of  the  thiazole  was  dissolved  in  100  cc.  of  cone,  sulfuric  acid.  This  solu- 
tion was  stirred  and  the  temperature  kept  at  75°  while  a  mixture  of  15  g.  (0.12  mole) 
of  cone,  nitric  acid  and  20  g.  of  cone,  sulfuric  acid  was  added  drop  by  drop.  The  stirring 
.was  continued  for  half  an  hour  after  all  of  the  nitric  acid  had  been  added.  Then  the 
mixture  was  heated  at  100°  for  an  hour,  allowed  to  cool,  poured  into  1500  cc.  of  cold 
water,  the  precipitate  collected  and  crystallized  from  glacial  acetic  acid  as  yellow  needles, 
m.  p.  188°  (corr.) ;  yield,  25  g.,  or  98%.  Both  Hofmann8  and  Naegeli4  give  the  melting 
point  as  188°. 

FUSION  OF  THE  NITRO  DERIVATIVE  WITH  CAUSTIC  ALKALI. — Ten  g.  of  this  nitro 
compound,  20  g.  of  potassium  hydroxide  and  40  g.  of  water,  were  heated  together  for  15 
minutes  at  200-210  °.  After  cooling  the  solution,  it  was  diluted,  the  tar  removed  and  the 
filtrate  acidified.  A  trace  of  colorless  solid  separated,  insufficient  to  recrystallize  or 
purify;  it  did  not  melt  sharply  but  began  to  soften  in  the  vicinity  of  100°.  Naegeli 
believed  that  he  isolated  £-nitrobenzoic  acid  (m.  p.  238°)  from  this  material  but  we 
failed  to  confirm  this,  although  4  times  as  much  initial  material  was  used  by  us. 

6-Amino-2-phenyl-benzothiazole,  C«H8NS(NHj),  (Formula  VI). — Twenty -five 
and  six- tenths  g.  (0.1  mole)  of  nitro  derivative  and  40  g.  (0.33  mole)  of  granular  tin  were 
covered  with  150  cc.  of  cone,  hydrochloric  acid,  and  the  flask  warmed  to  start  the  reac- 
tion. The  reduction  proceeded  with  evolution  of  so  much  heat  that  it  was  necessary 
to  chill  the  flask.  On  completion  of  the  reduction  the  solution  was  allowed  to  cool  and 
crystals  of  the  double  tin  salt  separated.  The  mixture  was  made  strongly  alkaline,  the 
precipitated  base  collected,  washed  with  3  N  sodium  hydroxide  solution  (to  remove  tin 
salts)  and  then  with  water.  The  crude  base,  crystallized  from  aniline  and  finally  from 
toluene,  gave  colorless  needles,  m.  p.  207°  (corr.);  yield,  16  g.  or  71%. 

Analyses.     Calc.  for  CiSH10N2S:  N,  12.39.     Found:   12.34,  12.43. 

This  amine  is  practically  insoluble  in  water,  in  dilute  acids,  or  in  concentrated 
hydrochloric  acid;  difficultly  soluble  in  methyl,  in  ethyl  or  in  tso-amyl  alcohol,  ethyl  or 
iso-amyl  acetate,  chloroform,  carbon  tetrachloride,  benzene  or  toluene,  and  still  more 
difficultly  soluble  in  ether.  Dilution  with  ether  generally  precipitates  it  from  solution 

17  Ziegler,  Ber.,  23,  2476  (1890);  Ger.  pat.  51,172;  Friedldnder,  2,  301  (1891). 


•      13 

in  other  solvents.  Its  alcoholic  solutions  show  a  beautiful  blue  fluorescence,  and  even 
ether  takes  up  sufficient  to  show  this  fluorescence,  too. 

ACETYL  DERIVATIVE. — From  the  base  and  acetic  anhydride  the  acetyl  derivative 
crystallizes  in  cubes,  m.  p.  214°  (corr.). 

Analyses.     Calc.  for  Ci5H]2ON2S:   N,  10.43.     Found:    10.49,  10.57. 

FUSION  OP  THE  AMINE  WITH  CAUSTIC  ALKALI. — Fifteen  g.  of  amine  and  60  g.  of 
moist  potassium  hydroxide  were  fused  for  15  minutes  at  as  low  a  temperature  as  possible. 
The  cool  melt  was  dissolved  in  water,  filtered,  the  filtrate  acidified,  and  the  precipitate 
crystallized  from  water.  It  melted  at  122°,  and  was  free  from  nitrogen  and  sulfur. 
Mixed  with  pure  benzoic  acid,  the  melting  point  remained  unchanged.  Some  of  it  was 
dissolved  in  absolute  alcohol,  the  solution  saturated  with  dry  hydrogen  chloride,  and 
water  then  added.  Upon  treatment  with  sodium  carbonate  solution,  oily  droplets 
separated  which  had  the  odor  characteristic  of  ethyl  benzoate. 

^-Nitrobenzene-axo-(6-amino-2-phenyl-benzothiazole),  O2N.C6H4.N :  N.Ci3H7NS- 
(NH2). — Two  and  three-quarters  g.  of  />-nitro-aniline  was  diazotized  and  the  solution 
poured  into  a  suspension  of  4.5  g,  of  the  aminothiazole  in  100  cc.  of  1 : 10  g.  hydrochloric 
acid.  The  mixture  was  cooled  and  stirred  for  an  hour;  then  the  brown  precipitate  was 
collected,  washed  with  water,  crystallized  from  aniline,  and  the  aniline  removed  by  dil. 
hydrochloric  acid.  Red  needles,  melting  at  196°  (corr.)  were  obtained.  They  were 
difficultly  soluble  in  aniline  or  in  nitrobenzene,  and  practically  insoluble  in  most  other 
organic  solvents;  yield,  5  g.,  or  67%. 

Analyses.     Calc.  for  Ci9H18O2N5S:  N,  18.67.     Found:   18.70,  18.75. 

ATTEMPTED  FURTHER  COUPLING. — Two  and  three-quarters  g.  of  £-nitro-aniline  was 
diazotized  and  allowed  to  act  upon  the  amine  as  before.  To  this  solution,  an  equal 
amount  of  diazotized  £-nitro-aniline  was  added,  while  the  temperature  was  kept  below 
5°  and  the  mixture  was  stirred  vigorously  for  half  an  hour.  The  brown  precipitate  ob- 
tained by  the  first  coupling  remained  unchanged.  The  mixture  was  then  filtered  and  the 
filtrate  divided  into  two  parts.  The  precipitate  was  washed  thoroughly  with  water  and 
crystallized  from  aniline,  when  it  melted  at  194-195°  (corr.).  Mixed  with  the  product 
from  the  previous  experiment,  the  melting  point  was  195°+  (corr.).  One  part  of  the 
filtrate  from  the  brown  precipitate  was  made  alkaline,  but  no  change  was  observed. 
The  other  portion  was  added  to  an  alkaline  solution  of  phenol,  causing  an  immediate 
intense  red  color  and  the  formation  of  an  orange  precipitate  on  acidification,  which 
proved  the  presence  of  unaltered  diazo-£-nitro-aniline.  Hence,  the  original  amine 
couples  but  once. 

ACETYL  DERIVATIVE. — This  was  obtained  from  the  azo  derivative  and  acetic 
anhydride  as  golden-yellow  plates,  m.  p.  203°  (corr.). 

Analyses.     Calc.  for  C2iHi5O3N6S:  N,  16.01.     Found:   16.01,  15.74. 

6-Benzalamino-2-phenyl-benzothiazole,  C6H6.CH:  N.Ci3H8NS. — Twenty-two  and 
six- tenths  g.  (0.1  mole)  of  aminothiazole  was  suspended  in  150  cc.  of  alcohol,  15  cc.  (0.15 
mole)  of  benzaldehyde  added  and  the  mixture  boiled  gently  for  an  hour;  the  solution 
boiled  with  bone  black,  filtered  and  cooled  gave  pale  yellow  plates,  m.  p.  151°  (corr.); 
yield,  30  $.,  or  96%. 

A  nalyses.     Calc.  for  C20Hi4N2S :  N,  8.92.     Found :  8.98,  8.81 . 

It  is  practically  insoluble  in  water,  and  difficultly  soluble  in  alcohol,  ethyl  or  isoamyl 
acetate,  ether,  choroform,  carbon  tetrachloride,  acetic  acid,  benzene  or  toluene. 

2,2/-Diphenyl-benzobisthiazole  (Formula  VIII). — Twenty  g.  of  this  benzalainino 
derivative  was  fused  with  10  g.  (5  equivalents)  of  sulfur  for  4  hours  at  250-60  °,  and  the 
heating  then  continued  for  an  hour  longer  under  diminished  pressure.  The  cold  melt 
was  pulverized,  and  extracted  repeatedly  with  hot  cone,  hydrochloric  acid.  The  acid 


14 

extract  (200  cc.)  was  poured  into  1  liter  of  water,  and  the  precipitate  collected  and 
crystallized  from  acetic  acid  giving  pale  yellow  needles,  m.  p.  235°  (corr.);  yield,  7  g.  or 
32%. 

Analyses.     Calc.  for  CwHuNzSj:  N,  8.14.     Found:  8.08,  8.17. 

Green  and  Perkin10  prepared  a  diphenyl-benzobisthiazole,  from  £-phenylenediamine 
dithiosulfonic  acid  and  benzaldehyde,  which  crystallized  from  amyl  alcohol  in  pale  straw 
colored  needles,  m.  p.  232-4°,  and  which  appears  to  be  identical  with  the  compound 
described  above. 

4-Nitro-2, 2 '-diphenyl-benzobisthiazole,  OjN.C2oHnN2Si.— Five  g.  of  the  above 
bisthiazole  was  dissolved  in  20  cc.  of  cone,  sulfuric  acid,  3  cc.  of  cone,  nitric  acid  added 
slowly,  the  solution  left  at  room  temperature  for  half  an  hour,  then  heated  at  100°  for 
an  hour,  cooled,  and  poured  into  200  cc.  of  ice  water.  The  yellow  precipitate  was  col- 
lected, crystallized  from  nitrobenzene,  washed  with  methyl  alcohol  (to  remove  the 
solvent)  and  dried  giving  a  yield  of  4  g.,  or  70%  of  yellow  needles,  m.  p.  262°  (corr.). 
The  substance  is  difficultly  soluble  or  insoluble  in  methyl,  ethyl  or  *'soamyl  alcohol, 
ethyl  or  isoamy]  acetate,  ether,  acetic  acid  or  anhydride,  chloroform  or  carbon  tetra- 
chloride,  benzene,  toluene  or  xylene. 

Analyses.     Calc.  for  C,oHnO2N,S,:  N,  10.80.     Found:   10.93,  10.95 

4-Amino-2,2 '-diphenyl-benzobisthiazole  was  prepared  by  boiling  3  g.  of  the  nitro 
compound  for  several  hours  with  3.5  g.  of  tin  and  30  cc.  of  cone,  hydrochloric  acid,  until 
the  reduction  was  complete.  The  solution  was  made  strongly  alkaline  with  sodium 
hydroxide,  the  precipitated  base  collected  on  a  filter,  crystallized  from  aniline,  the  crys- 
tals were  washed  free  from  aniline  by  dil.  hydrochloric  acid,  then  washed  with  dil. 
ammonia  and  dried  over  cone,  sulfuric  acid.  A  yield  of  2  g.,  or  72%,  of  yellowish 
needles  was  obtained;  m.  p.  285-287°  (corr.). 

Analyses      Calc.  for  CwHuNjS,:  N,  11.70      Found:    11.93,11.98. 

ACETYL  DERIVATIVE. — This  was  obtained  from  the  amine  and  acetic  anhydride 
and  forms  colorless  plates,  m.  p.  250-253°  (corr.). 

Analysis.     Calc.  for  CMHi6ONjS2 :  N,  10.47.     Found:   10.62. 

FUSION  OF  THE  AMINB  WITH  CAUSTIC  ALKALI. — One  g.  of  this  amine  was  fused 
with  4  g.  of  moist  potassium  hydroxide  at  a  low  temperature  for  10  minutes,  the  melt 
allowed  to  cool,  dissolved  in  25  cc.  of  water,  filtered  and  the  filtrate  acidified  with 
hydrochloric  acid.  The  precipitate  obtained  was  removed  and  crystallized  from  water. 
It  proved  to  be  benzoic  acid  (m.  p.  122°).  The  filtrate  was  neutralized  with  ammonia, 
evaporated  to  dryness  on  the  water-bath,  the  residue  warmed  with  5  cc.  of  acetic  an- 
hydride, the  solution  filtered  through  glass  wool,  and  the  filtrate  carefully  diluted. 
No  acetamino-benzoic  acid  was  obtained.  Therefore  the  amino  group  must  have  been 
on  the  central  benzene  nucleus  and  not  on  either  the  2-  or  2'-phenyl  nucleus. 

6-Dimethylamino-2-phenyl-benzothiazole,  (CHs^N.CisHgNS. — Ten  g.  of  6-amino- 
2-phenyl-benzothiazole,  6  cc.  of  cone,  hydrochloric  acid  and  20  cc.  of  absolute  methyl 
alcohol  were  heated  together  in  a  sealed  tube  at  175°  for  24  hours.  The  tube  then 
contained  a  red  viscous  liquid  which,  on  standing,  deposited  reddish-brown  needles 
which  were  recrystallized  from  acetone  and  then  melted  at  185  (corr.);  yield,  4  g.,  or 
36%. 

Analyses.     Calc.  for  C^HuNzS:  N,  11.03.     Found:   11.21,11.11. 

No  methyl  chloride  addition  product  was  found. 

2-Phenyl-benzothiazole  Tetrabromide,  CiSH»NSBr4. — Ten  g.  of  2-phenyl-benzo- 
thiazole  -was  dissolved  in  250  cc.  of  acetic  acid,  10  cc.  of  bromine  (2  molec.  equivalents) 
added,  the  mixture  shaken  vigorously  for  10  minutes  and  allowed  to  stand  for  half  an 
hour.  Red  needles  separated  which  were  collected  and  dried  over  potassium  hydroxide 


15 

in  vacua.  The  compound  is  quite  unstable,  giving  off  bromine  on  standing.  The 
crystals  were  therefore  dried  for  only  half  an  hour.  The  substance  melted  in  the 
neighborhood  of  125°,  with  considerable  decomposition;  yield,  15  g.,  or  60%. 

Analyses.  Calc.  for  Ci3H9NSBr4:  N,  2.64;  Br,  60.22.  Found  N,  2.68,  2.80; 
Br.  59.95. 

Bromine  was  determined  by  adding  the  sample  to  a  very  dilute  sodium  hydrogen 
sulfite  solution,  filtering  out  the  liberated  2-phe,nyl-benzothiazole,  acidifying  the  filtrate 
and  precipitating  the  bromine  ion  as  silver  bromide. 

6-Bromo-2-phenyl-benzothiazole,  Br.Ci3H8NS. — In  a  subsequent  experiment 
for  the  preparation  of  the  above  tetrabromide,  the  acetic  acid  solution  of  the  thiazole 
(10  g.)  and  bromine  (10  cc.)  was  diluted  with  150  cc.  of  water  and  warmed  to  complete 
the  solution.  The  effect  of  this  dilution  and  warming,  however,  caused  a  sudden  change 
in  the  course  of  the  reaction ;  the  red  color  of  the  solution  disappeared,  with  evolution  of 
bromine,  and  a  colorless  solid  separated  which  crystallized  in  plates  as  the  material 
cooled.  These  were  recrystallized  from  acetic  acid,  and  proved  to  be  a  monobromo 
substitution  product,  m.  p.  152°  (corr.);  yield,  13  g.,  or  94%. 

Analyses.  Calc.  for  Ci3H8NSBr:  C,  53.79;  H,  2.78;  N,  4.83;  S,  11.05;  Br,  27.55. 
Found:  C,  54.44;  H,  3.03;  N,  4.79;  S,  11.08;  Br,  27.28. 

The  results  of  nitration  led  us  to  infer  that  the  bromine  also  had  entered  Position  6 
on  the  nucleus.  In  order  to  confirm  this  conclusion  11.3  g.  (0.05  mole)  of  the 
6  amino  derivative  was  suspended  in  a  mixture  of  50  cc.  of  water  and  10  cc.  of  cone, 
sulfuric  acid  at  0°,  and  4  g.  of  sodium  nitrite  (0.05  mole)  dissolved  in  20  cc.  of 
water  added  slowly  while  the  mixture  was  cooled  and  stirred  mechanically.  When 
the  diazotization  was  completed,  25  g.  of  potassium  bromide  was  added  and  then 
(very  slowly)  10  g  of  copper  powder.  The  ice-cold  solution  was  gradually  heated  to 
boiling  and  kept  at  this  temperature  for  half  an  hour ;  then  it  was  cooled,  the  precipitated 
bromo  derivative  collected  and  crystallized  twice  from  acetic  acid,  when  it  melted  at 
152°  (corr.).  Mixed  with  the  compound  obtained  above  from  the  tetrabromide,  the 
melting  point  remained  unaltered;  yield,  3  g.,  or  21%. 

Analysis.     Calc.  for  Ci3H8NSBr:   N,  4.83.     Found:   4.89. 

2-Phenyl-benzothiazole-di-iodide,  Ci3H9NSl2. — Twenty-one  and  one-tenth  g. 
(0.1  mole)  of  2-phenyl-benzothiazole  was  dissolved  in  acetic  acid  and  a  solution  of 
50.8  g.  (0.2  mole)  of  iodine  in  the  same  solvent  was  added.  The  mixture  was  shaken 
for  half  an  hour  and  then  allowed  to  stand  for  several  hours.  A  trace  of  crystalline 
material  separated.  An  additional  21.1  g.  of  thiazole  was  then  introduced.  The 
solution  soon  deposited  a  large  amount  of  glistening  black  needles,  which  were  removed, 
washed  with  acetic  acid,  then  with  water,  and  dried  over  potassium  hydroxide  under 
diminished  pressure,  when  they  melted  at  84.5°  (corr.) ;  yield,  78  g.,  or  85%. 

Analyses.     Calc.  for  Ci3H9NSI2:   I,  54.58.     Found:   55.05,  54.98. 

This  addition  product  is  quite  unstable,  and  sodium  thiosulfate  removes  its  iodine 
quantitatively . 

6-Cyano-2-phenyl-benzothiazole,  NC.Ci3H8NS. — Fifty  g.  of  cupric  sulfate  penta- 
hydrate  was  dissolved  in  100  cc.  of  warm  water,  a  solution  of  55  g.  of  potassium  cyanide 
in  100  cc.  of  water  was  added,  the  mixture  was  heated  to  boiling  and  a  suspension  of  the 
diazotized  amine  (prepared  by  adding  a  solution  of  14  g.  of  sodium  nitrite  in  50  cc  of 
water  to  a  suspension  of  45.3  g.  of  amine  in  a  mixture  of  150  cc.  of  water  and  50  cc.  of 
hydrochloric  acid  and  stirring  for  half  an  hour)  added  very  slowly  with  active  stirring. 
The  mixture  was  boiled  for  half  an  hour  longer,  cooled  and  the  precipitated  nitrile 
collected.  It  is  difficultly  soluble  or  insoluble  in  ethyl  or  isoamyl  alcohol  or  acetate, 
benzene,  toluene  or  xylene,  nitrobenzene,  acetic  acid,  chloroform  or  carbon  tetrachloride, 
and  no  good  crystallizing  medium  was  found  for  it. 


16 

2-Phenyl-benzothiazole-6-carboxylic  Acid,  (Formula  XIII),  Ci3H8NS.COOH.— 
The  crude  nitrile  obtained  above  was  boiled  under  a  reflux  condenser  with  a  mixture  of 
100  cc.  of  cone,  sulfuric  acid  and  60  cc.  of  water,  until  a  test  portion  dissolved  completely 
in  dil.  sodium  hydroxide  (about  15  hours).  The  solution  was  then  cooled,  poured  into 
2  liters  of  cold  water  and  the  precipitated  acid  removed.  As  no  satisfactory  neutral 
solvent  could  be  found  for  crystallizing,  it  was  dissolved  in  dil.  sodium  hydroxide  and 
converted  into  the  methyl  ester  by  adding  50  g.  (0.4  mole;  twice  the  calculated  amount) 
of  dimethyl  sulfate  drop  by  drop,  with  simultaneous  addition  of  sufficient  dil.  sodium 
hydroxide  solution  to  keep  the  solution  faintly  alkaline.  After  stirring  the  mixture  for 
an  hour  to  insure  destruction  of  all  of  the  excess  of  dimethyl  sulfate  the  separated 
thiazole  methyl  ester  was  filtered  out,  dissolved  in  alcohol,  the  solution  boiled  with  bone 
black,  and  the  ester  crystallized  to  constant  melting  point,  giving  minute  prisms  of  pale 
yellowish  tinge,  m.  p.  153-154°  (corr.);  yield,  7  g.,  or  13%. 

Analyses      Calc.  for  CuHnOsNS:  N,  5.20.     Found:  5.11.  5.50. 

This  purified  ester  was  saponified  by  boiling  6  g.  of  it  with  200  cc  of  10%  aqueous 
sodium  hydroxide  until  all  of  it  had  dissolved.  The  hot  solution  was  then  boiled  with 
bone  black,  filtered,  the  filtrate  acidified  with  hydrochloric  acid,  the  precipitated 
thiazole  acid  removed,  washed  and  dried  at  120°  giving  a  slightly  grayish  powder,  m.  p. 
261-263°  (corr.)  with  decomposition;  yield,  5  g.,  or  88%  calculated  to  the  ester,  or  11% 
calculated  back  to  the  original  amine: 


Acetyl  Chloride  Addition  Product  of  2-Phenyl-benzothiazole,          Cl         COCHs. 
— (On  adding  5  g.  of  acetyl  chloride  to  a  solution  of  5  g.  of  2-phenyl-benzothiazole  in  25  cc. 
of  toluene,  white  leaflets  of  the  addition  product  separated,  amounting  to  5  g.  (73%). 
The  substance  lost  the  acetyl  chloride  very  easily  when  it  was  warmed,  so  that  the  melt- 
ing point  obtained  is  that  of  the  thiazole  itself  (114°). 

It  was  analyzed  by  agitating  it  with  water,  filtering  out  the  precipitated" thiazole, 
and  determining  the  chlorine  in  the  filtrate  with  silver  nitrate. 

Analyses.     Calc.  for  CwHuONSCl:   Cl,  12.24.     Found:    11.98,12.19. 

Summary 

1.  An  improved  method  is  given  for  the  preparation   of  2-phenyl- 
benzothiazole  in  considerable  quantities. 

2.  The    product    obtained    by    nitration    of    2-phenyl-benzothiazole 
is  shown  to  be  the  6-nitro  derivative  by  conversion,  through  the  amine 
and  its  benzal  derivative,  into  2,  2'-diphenyl-benzobisthiazole.     Hitherto 
the  nitro  group  has  been  assigned  position  4'  on  the  2-phenyl  nucleus. 

3.  The  position  of  the  amine  group  was  further  established  by  coupling 
it  but  once  with  diazotized  p-nitro-aniline. 

4.  Nitro  and  amino  derivatives  of  the  2,2/-diphenyl-benzobisthiazole 
were  prepared  and  the  positions  of  the  groups  determined. 

5.  2-Phenyl-benzothiazole  adds  4  bromine  atoms  directly.     The  tetra- 
bromide  lost  bromine  and  hydrogen  bromide  when  boiled  with  dil.  acetic 
acid  to  form  6-bromo-2-phenyl-benzothiazole,   which  was  also  produced 
from  the  6-amino  derivative.     With  iodine,  only  2  atoms  are  taken  up; 
an  unstable  di-iodide  results. 


17 

6.  The  addition  product  of  2-phenyl-benzothiazole  and  acetyl  chloride 
loses  acetyl  chloride  readily  when  heated  or  on  treatment  with  water. 

7.  6-Amino-2-phenyl-benzothiazole    was    changed   into   the   cyanide, 
and  the  latter  into  the  6-carboxylic  acid,  which  is  structurally  analogous 
to  Cinchophen  ( Atophan) ,  and  which  it  is  hoped  may  show  useful  thera- 
peutic  properties. 


CHRONOLOGICAL  BIBLIOGRAPHY. 

1877— Leo,  Ber.,  10,  2133. 

1879— Hofmann,  Ber.,  12,  2360. 

1880— Hofmann,  Ber.,  13,  8,  17,  1223,  1236. 

1882— Tiemann  &  Piest,  Ber.,  15,  2033. 

1886— Jacobson,  Ber.,  19,  1068,  1069. 

1889— Gatterman,  Ber.,  22,  422. 

1890— Wallach,  Ann.,  259,  401. 

Ziegler,  Ber.,  23,  2476. 

Hantsch,  Ber.,  23,  2774. 
1891— Ger.  Pat.  51,  738,  Friedldnder,  2,  299! 

Ger.  Pat.  51,  172,  Friedldnder,  2,  301. 

Ger.  Pat.  55,  222,  Friedldnder,  2,  302. 

Ger.  Pat.  50,  486,  Friedldnder,  2,  303. 

Ger.  Pat.  54,  921,  Friedldnder,  2,  305. 
1894— Naegeli,  Bull.  soc.  chim.  [3]  11,  895. 
1895— Wheeler,  Am.  Chem.  J.,  17,  1401. 
1896— Ger.  Pat.  57,  557,  Friedldnder,  3,  750. 

Ger.  Pat.  58,  641,  Friedldnder,  3,  765. 
1899— Kym,  Ber.,  32,  3532. 

Ger.  Pat.  75,  674,  Friedldnder,  4,  325. 

Ger.  Pat.  79,  214,  Friedldnder,  4,  829. 

Ger.  Pat.  81,  711,  Friedldnder,  4,  831. 
1902— Voswinckel,  Ber.,  35,  1946. 
1903— Green  &  Perkin,  J.  C.  S.,  83,  1204. 
1905 — Reissert,  Ber.,  38,  3433. 
1910— Fr.  Pat.  216,086,  Winther,  3,  379. 
1911— Reissert  &  Holle,  Ber.,  44,  3035. 
1913 — Fromm  &  Martin,  Ann.,  401,  1781. 

Ciusa  &  Luzzatto,  Atti  accad.  Lincei,  [5]  22,  I,  306. 

Ciusa  &  Luzzatto,  Zentr.  II,  1318. 
1914 — Ciusa  &  Luzzatto,  Gazz.  chim.  ital.,  44,  I,  64. 
1915— Zincke  &  Siebert,  Ber.,  48,  1244,  1251. 


VITA. 

Emanuel  M.  Abrahamson  was  born  in  Brooklyn,  N.  Y.,  on  June  25, 
1897.  After  a  preliminary  education  in  the  schools  of  that  Borough  he 
entered  Columbia  College  in  1914,  from  which  he  received  the  degree  of 
B.  S.  (cum  laude]  in  1917.  He  then  studied  Chemical  Engineering  in  the 
School  of  Mines,  Engineering  and  Chemistry  of  Columbia  University, 
receiving  the  degree  of  Ch.  E.  in  1918.  Upon  his  graduation,  he  entered 
the  Chemical  Warfare  vService,  U.  S.  A.  and  was  stationed  at  Edgewood 
Arsenal.  After  his  discharge  from  the  army,  he  re-entered  Columbia 
University  to  pursue  studies  under  the  Faculty  of  Pure  Science.  He  was 
awarded  the  degree  of  M.  A.  in  1920.  From  1918  to  1921  he  held  the 
position  of  assistant  in  the  Department  of  Chemistry  of  Columbia  Uni- 
versity. 


Abrahar 

Investi^r 
thiazolo    fit 


478712 

it  ion  in   the 
Id 


QD403 

A2 


478712 


4-0 


UNIVERSITY  OF  CALIFORNIA  LIBRARY 


